Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice

2019 ◽  
Vol 109 (4) ◽  
pp. 374-390 ◽  
Author(s):  
Eglantine Balland ◽  
Weiyi Chen ◽  
Tony Tiganis ◽  
Michael A. Cowley
Keyword(s):  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Inhibitory Effect ◽  
Obese Mice ◽  
Leptin Signaling ◽  
Insulin Tolerance ◽  
Hormonal Resistance ◽  
Receptor Neurons

Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.

Abstract 17023: Adipose Tissue Specific Temporal Deletion of Ager Induces Weight Loss in Diet Induced Obese Mice and Improves Glucose Homeostasis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Robin Wilson ◽  
Lakshmi Arivazhagan ◽  
Henry Ruiz ◽  
Jay Pendse ◽  
Laura Frye ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Fasting Glucose ◽  
Obese Mice ◽  
Gene Encoding ◽  
Low Fat Diet ◽  
Insulin Tolerance ◽  
Specific Deletion

Introduction: The incidence of obesity and its comorbidities is increasing at an alarming rate in US and around the globe. Our previous studies showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and insulin resistance (IR), as global Ager (gene encoding RAGE) and adipocyte-specific Ager- deleted mice fed a high fat diet (HFD) showed protection from weight gain and IR. However, the role of Ager deletion in mice with established obesity, switched to low fat diet has not been tested. We hypothesize that temporal adipocyte-specific deletion of Ager in obese mice could enhance weight loss and improves glucose homeostasis. Methods: Mice with conditional adipocyte-specific Ager deletion were generated by breeding Ager flox/flox mice with AdipoQ ERT2 Cre recombinase mice resulting in Ager flox/flox / AdipoQ ERT2 Cre (+) and Cre (-) animals. Mice were fed HFD (60% kcal/fat) for 20 weeks starting at 8 weeks of age to establish obesity and were then treated with tamoxifen (TAM) (75 mg/kg per day x 3 alternative days) to induce deletion of Ager . After 4 weeks of TAM treatment, mice were switched to standard chow for 7 weeks and body weight was monitored regularly. Fasting glucose, insulin and glucose tolerance was measured. Results: After 7 weeks of switching to standard chow following TAM, Cre (+) lost significantly more body weight whereas Cre (-) mice showed no significant weight loss over 7 weeks. Furthermore, Cre (+) mice exhibited significantly higher food intake, lower fasting glucose, lower epididymal and inguinal white adipose tissue weights, and improved glucose and insulin tolerance compared to Cre (-) mice. Conclusions: Temporal adipocyte-specific deletion of Ager in mice with established obesity promotes weight loss and improves glucose homeostasis. RAGE may act as a novel therapeutic target in obesity.

scholarly journals Leptin Action in the Ventromedial Hypothalamic Nucleus Is Sufficient, But Not Necessary, to Normalize Diabetic Hyperglycemia

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3067-3076 ◽  
Author(s):  
Thomas H. Meek ◽  
Miles E. Matsen ◽  
Mauricio D. Dorfman ◽  
Stephan J. Guyenet ◽  
Vincent Damian ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Leptin Receptor ◽  
Brain Area ◽  
Receptor Gene ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hypothalamic Nucleus ◽  
Leptin Signaling ◽  
Brown Adipose ◽  
Tracer Dilution

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

scholarly journals Leptin Signaling in the Arcuate Nucleus Reduces Insulin’s Capacity to Suppress Hepatic Glucose Production in Obese Mice

Cell Reports ◽  
2019 ◽  
Vol 26 (2) ◽  
pp. 346-355.e3 ◽  
Author(s):  
Eglantine Balland ◽  
Weiyi Chen ◽  
Garron T. Dodd ◽  
Gregory Conductier ◽  
Roberto Coppari ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Obese Mice ◽  
Leptin Signaling ◽  
Hepatic Glucose

scholarly journals Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2016-2024 ◽  
Author(s):  
Gregory J. Morton ◽  
Kevin D. Niswender ◽  
Christopher J. Rhodes ◽  
Martin G. Myers ◽  
James E. Blevins ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Wild Type ◽  
Leptin Signaling ◽  
Adenoviral Gene Therapy

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, leprb, in the ARC of leptin receptor-deficient Koletsky (fak/fak) rats. Successful expression of adenovirus containing leprb (Ad-leprb) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-leprb into the ARC restored low hypothalamic levels of leprb mRNA to values approximating those of wild-type (Fak/Fak) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fak/fak rats injected with a control adenovirus (Ad-lacZ) (P < 0.05 for each comparison). In contrast, Ad-leprb delivery to either the lateral hypothalamic area of fak/fak rats or to the ARC of wild-type Fak/Fak rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

scholarly journals Long-term consequences of the absence of leptin signaling in early life

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Angela M Ramos-Lobo ◽  
Pryscila DS Teixeira ◽  
Isadora C Furigo ◽  
Helen M Melo ◽  
Natalia de M Lyra e Silva ◽  
...  
Keyword(s):  
Early Life ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Brain Growth ◽  
Leptin Signaling ◽  
Developmental Problems ◽  
The Poor ◽  
Long Term Consequences

Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.

scholarly journals Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction

2013 ◽  
Vol 305 (12) ◽  
pp. E1512-E1520 ◽  
Author(s):  
Sharone Sheffer-Babila ◽  
Yan Sun ◽  
Davelene D. Israel ◽  
Shun-Mei Liu ◽  
Genevieve Neal-Perry ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Vaginal Opening ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Wild Type Female ◽  
Hypothalamic Arcuate Nucleus

Deficient leptin signaling causes infertility via reduced activity of GnRH neurons, causing a hypogonadal state in both rodents and humans. Because GnRH neurons do not express leptin receptors, leptin's effect on GnRH neurons must be indirect. Neurons within the hypothalamic arcuate nucleus that coexpress AGRP and NPY are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. Previously, we reported that the absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant ( Lepr db/db ) females result in restoration of fertility and lactation despite the persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 (NKB)-TAC3R signaling plays a role in puberty maturation and is modulated by metabolic status, the other aim of this study is to test whether TAC2/NKB neurons in ARC regulated by melanocortinergic signals herein affect leptin's action on puberty and reproduction. Our data showed that AGRP deficiency in Lepr db/db females restores normal timing of vaginal opening and estrous cycling, although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp−/− Lepr db/db females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. The postpubertal increase in hypothalamic TAC2 mRNA was not observed in Lepr db/db females, whereas AGRP deficiency restored it in Lepr db/ db females. Additionally, MC4R activation with MTII induced FOS expression in TAC2 neurons, supporting the concept of melanocortinergic regulation of TAC2 neurons. These studies suggest that AGRP imposes an inhibitory effect on puberty and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons.

scholarly journals 20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

2014 ◽  
Vol 223 (1) ◽  
pp. T25-T35 ◽  
Author(s):  
Margaret B Allison ◽  
Martin G Myers
Keyword(s):  
Energy Balance ◽  
Signaling Pathways ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Protein Tyrosine Phosphatases ◽  
Cytokine Signaling ◽  
Cellular Mechanisms ◽  
Leptin Signaling

Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling proteins and protein tyrosine phosphatases also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models that have been used to elucidate these functions in vivo.

scholarly journals Anorexigenic effect of cholecystokinin is lost but that of CART (Cocaine and Amphetamine Regulated Transcript) peptide is preserved in monosodium glutamate obese mice

2009 ◽  
pp. 717-723 ◽  
Author(s):  
B Železná ◽  
J Maixnerová ◽  
R Matyšková ◽  
R Haugvicová ◽  
D Blokešová ◽  
...  
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Monosodium Glutamate ◽  
Central Administration ◽  
Obese Mice ◽  
Male Mice ◽  
Short Term ◽  
Leptin Signaling ◽  
Cart Peptide ◽  
Anorexigenic Effect

Monosodium glutamate (MSG) treatment of neonatal mice results in a selective damage to the arcuate nucleus (ARC) and development of obesity with increased adiposity at sustained body weight in the adulthood. Feeding pattern of the MSG obese mice is unusual. Our previous results showed that after 24-h fasting, MSG mice consumed negligible amount of food in several hours and therefore, it was impossible to register the effect of peptides attenuating food intake such as cholecystokinin (CCK) or cocaine- and amphetamine-regulated transcript (CART) peptide. To overcome this problem, two findings were used: firstly, orexigenic effect of neuropeptide Y (NPY) was attenuated both by CCK or CART peptide in lean fed mice and secondly, orexigenic effect of NPY was preserved in fed rats with MSG obesity. In this study, short-term food intake in fed lean and MSG obese C57BL/6 male mice was measured after simultaneous central administration of orexigenic NPY with either CART peptide or peripherally administered CCK. Anorexigenic action of exogenous CART peptide was preserved in MSG obese mice. On the other hand, satiety effect of exogenous CCK was completely lost in MSG obese mice. In conclusion, effective leptin signaling in ARC is necessary for satiety effect of CCK.

Sign in / Sign up

Export Citation Format

Share Document